rs4888761

Variant names:

• chr16-78189092-G-A
• rs4888761
• NM_016373.4:c.516+24803G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-78189092-G-A
• chr16-78189092-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_016373.4(WWOX):​c.516+24803G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.35 in 151,904 control chromosomes in the GnomAD database, including 9,774 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.35 (9774 hom., cov: 32)
• Consequence: WWOX NM_016373.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.220
• Publications: 4 publications found

Genes affected

WWOX (HGNC:12799): (WW domain containing oxidoreductase) This gene encodes a member of the short-chain dehydrogenases/reductases (SDR) protein family. This gene spans the FRA16D common chromosomal fragile site and appears to function as a tumor suppressor gene. Expression of the encoded protein is able to induce apoptosis, while defects in this gene are associated with multiple types of cancer. Disruption of this gene is also associated with autosomal recessive spinocerebellar ataxia 12. Disruption of a similar gene in mouse results in impaired steroidogenesis, additionally suggesting a metabolic function for the protein. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]

WWOX Gene-Disease associations (from GenCC):

• genetic developmental and epileptic encephalopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive spinocerebellar ataxia 12

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• developmental and epileptic encephalopathy, 28

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• 46,XY partial gonadal dysgenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.501 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016373.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WWOX	NM_016373.4	MANE Select	c.516+24803G>A		intron	N/A	NP_057457.1
	WWOX	NM_001291997.2		c.177+24803G>A		intron	N/A	NP_001278926.1
	WWOX	NM_130791.5		c.516+24803G>A		intron	N/A	NP_570607.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WWOX	ENST00000566780.6	TSL:1 MANE Select	c.516+24803G>A		intron	N/A	ENSP00000457230.1
	WWOX	ENST00000408984.7	TSL:1	c.516+24803G>A		intron	N/A	ENSP00000386161.3
	WWOX	ENST00000402655.6	TSL:1	c.409+73938G>A		intron	N/A	ENSP00000384238.2

Frequencies

GnomAD3 genomes AF: 0.350 AC: 53083 AN: 151786 Hom.: 9766 Cov.: 32

Gnomad AFR AF: 0.216

Gnomad AMI AF: 0.388

Gnomad AMR AF: 0.415

Gnomad ASJ AF: 0.428

Gnomad EAS AF: 0.517

Gnomad SAS AF: 0.400

Gnomad FIN AF: 0.410

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.386

Gnomad OTH AF: 0.359

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.350 AC: 53120 AN: 151904 Hom.: 9774 Cov.: 32 AF XY: 0.353 AC XY: 26218 AN XY: 74220

African (AFR) AF: 0.217 AC: 8976 AN: 41454

American (AMR) AF: 0.416 AC: 6346 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.428 AC: 1483 AN: 3464

East Asian (EAS) AF: 0.517 AC: 2660 AN: 5144

South Asian (SAS) AF: 0.400 AC: 1920 AN: 4802

European-Finnish (FIN) AF: 0.410 AC: 4329 AN: 10552

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.386 AC: 26200 AN: 67906

Other (OTH) AF: 0.358 AC: 755 AN: 2110

Alfa AF: 0.356 Hom.: 6284

Bravo AF: 0.347

Asia WGS AF: 0.429 AC: 1494 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	3.5
DANN	Benign	0.49
PhyloP100		0.22
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4888761; hg19: chr16-78222989;